Compositions for sleeping disorders

ABSTRACT

Provided herein is a method for treating, preventing, or ameliorating a disorder such as insomnia or another sleeping disorder using a composition that contains an effective amount of one or more compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 11/129,628, filed on Mar. 13, 2005, which claims the benefit of U.S.provisional application No. 60/572,528 filed on May 18, 2004. Theteachings in these applications are incorporated herein in theirentirety by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention generally relates to a composition for treating,preventing or ameliorating insomnia and other sleeping disorders.

2. Description of the Background

A large percentage of the adult population suffers from insomnia in someform at some time in their lives. This may vary from a single episode ofone night's duration to chronic conditions. Transient insomnia is aninsomnia that is present for one to several days, and is less than oneweek in duration. Short term insomnia is an insomnia of one to threeweeks in duration. Chronic insomnia is typically accepted to involveepisodes greater than three (3) weeks in duration. The insomnia mayfurther involve onset insomnia (difficulty in falling asleep) and/ormaintenance insomnia (difficulty in maintaining uninterrupted sleep). Itis well known that the sleep deprivation resulting from such insomniaadversely affects cognition, safety and quality of life.

Known treatments for insomnia include the administration of medication,either of the non-barbiturate or barbiturate type, shortly beforebedtime. While both types of sedatives may be used to effectively treatinsomnia, neither is without its undesirable side effects. Barbituratetype sedatives, such as secobarbital (sold by Eli Lilly and Companyunder the trade name of Seconal.®.) are general depressants. Whileeffective, these medications are well known to lose their effectivenessafter a few days. Furthermore, they are highly addictive and commonlyabused.

The groups of medications now most commonly used for the treatment ofinsomnia are the imidazopyridines, the pyrazolopyrimidines and thebenzodiazepines. There is one available hypnotic in the imidazopyridinegroup, one in the pyrazolopyrimidine group and there are five in thebenzodiazepine group. They differ significantly in half lives but areotherwise very similar and equally effective. They have supplanted thebarbiturates as the principal treatment for insomnia because they haveless addiction potential and are associated with less risk for suicidethan the barbiturates unless taken with alcohol. However, these groups,too, are addictive and their wide usage draws concern as their potentialside effects become more apparent. These side effects include daytimesedation, decreased cognitive abilities such as memory loss and, mostrecently in the case of Halcion.®. (triazolam) and possibly Ambien.®.(zolpidem) and Sonata.®. (zaleplon), feelings of agitation after thedrug's therapeutic effects pass.

Other pharmaceutical formulations, e.g., those described in U.S. Pat.Nos. 5,502,047, 5,643,897, 6,211,229, and 6,344,487 can be used fortreating insomnia with limited effectiveness.

Therefore, there is a need for new compositions effective for treatinginsomnia and related disorders.

The compositions and embodiments thereof described herein address theabove described problems and other needs.

SUMMARY OF THE INVENTION

Provided herein is a method for treating, preventing or amelioratinginsomnia and related disorders. The method comprises applying to asubject a composition that includes an effective amount of one or atleast two of myricitrin, a related compound, or a pharmaceuticallyacceptable salt thereof. The composition may also include aphysiologically acceptable carrier such as a pharmaceutically acceptablecarrier. The composition can be formulated into any formulation for adesired mode of administration. The composition can be used to treat adisorder such as insomnia, depression-related disease, stress-relateddisease, depression-related sleep disorder, neurodegeneration diseases,Alzheimer's disease, Pick's disease, spinocerbellar degeneration,Parkinson's disease, chorea, glaucoma, amyotrophic lateral sclerosis,senile macular degeneration, hepatic encephalopathy, demyelinatingdiseases, Lewy body dementia, multi-infarct dementia, multiple sclerosisor combinations thereof.

BRIEF DESCRIPTION OF FIGURES

FIG. 1A shows the structure of myricitrin; and FIG. 1B shows thestructure of myricetin.

FIG. 2 shows a method of hydroxylation and methylation of a compound ofFormula I.

FIG. 3 shows a method of inter-transformation of a compound of Formula Ito another compound as defined in Formula I.

FIG. 4 shows a further method of inter-transformation of a compound ofFormula I to another compound as defined in Formula I.

FIG. 5 shows a further method of inter-transformation of a compound ofFormula I to a compound of Formula III.

FIG. 6 shows effects of mixtures of dihydromyricetin, myricetin andmyricitrin on loss of righting reflex in male C57/B6 mice.

FIGS. 7A-7C shows the comparison of the effects of Compound Mixture,zolpidem and zopiclone versus vehicle treatment on sleep latency andquality.

DETAILED DESCRIPTION Compositions Including Myricitrin or RelatedCompounds

Provided herein is a method for treating, preventing or amelioratinginsomnia and related disorders using a composition. The composition caninclude an effective amount of myricitrin (FIG. 1A), a related compound,or a pharmaceutically acceptable salt thereof. The composition may alsoinclude a physiologically acceptable carrier such as a pharmaceuticallyacceptable carrier. The composition can be formulated into anyformulation for a desired mode of administration.

Myricitrin and Related Compounds

In one embodiment, the composition includes an effective amount acompound of formulae I or II:

in which R₁-R₁₃, R₂₀ and Z₁-Z₃ substituents are defined as follows:

R₁, R₂, and R₁₂ taken independently can be, for example, absence,hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule;

R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₃ and R₂₀ taken independentlycan be, for example, hydrogen, halo, alkyl, substituted alkyl, alkoxy,cycloalkyl, heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, thiol, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, cyano, isocyano, substitutedisocyano, carbonyl, substituted carbonyl, carboxyl, substitutedcarboxyl, amino, substituted amino, amido, substituted amido, fulfonyl,substituted sulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic,substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, polyether, polyester, polypeptide, protein,polyphosphazene, polyalkylene oxide, polyalkylene glycol, polyethyleneglycol, polyalkylene, a bioactive agent, or a drug molecule;

Z₁, Z₂ and Z₃ taken independently can be, for example, oxygen (O),sulphur (S), or NH;

Z₁ and R₁ taken together can be, for example, a moiety of formula III:

in which R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ taken independently can be forexample, hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; and

Z₄ can be oxygen (O), sulphur (S), or NH.

In some embodiments, any of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, Z₁, Z₂, Z₃ and Z₄ ofFormulae I or II can exclude any of the groups provided herein. Forexample, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₄, R₁₅,R₁₆, R₁₇, R₁₈, R₁₉, Z₁, Z₂, Z₃ and Z₄ of Formula I taken together do notform myricetin (FIG. 1B) or any of the compounds listed in WO0215901.Myricetin is also known as 3,3′,4′,5,5′,7-hexOH-Flavone, Cannabiscetin,myricetol, myricitin, or 3,3′,4′,5,5′,7-Hexahydroxyflavone.

In one embodiment, the compound of Formula I can be myricitrin (FIG.1A). Myricitrin is also known as myricetol 3-rhamnoside, myricitrine,myricitroside, myricetrin, or5,7-Dihydroxy-3-((2S,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyl-tetrahydro-pyran-2-yloxy)-2-(3,4,5-trihydroxy-phenyl)-1-benzopyran-4-one)and has a structure similar to that of myricetin (FIG. 1B).

The compound of formula II can be in a racemic form, a mixture ofdiastero isomers, or an enantiomer. The various enantiomers of thecompound of formula II are shown in formulae IIa, IIb, IIc and IId:

in which R₁-R₁₃, R₂₀ and Z₁-Z₃ substituents are defined above.

In one embodiment, the compound of formula II can be a compound offormula IIe:

in which R₁ can be, for example, hydrogen, halo, alkyl, substitutedalkyl, alkoxy, cycloalkyl, heterocyclic, alkenyl alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, phenyl, substitutedphenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,hydroxyl, alkoxy, substituted alkoxy, phenoxy, substituted phenoxy,aroxy, substituted aroxy, thiol, alkylthio, substituted alkylthio,phenylthio, substituted phenylthio, arylthio, substituted arylthio,cyano, isocyano, substituted isocyano, carbonyl, substituted carbonyl,carboxyl, substituted carboxyl, amino, substituted amino, amido,substituted amido, fulfonyl, substituted sulfonyl, polyaryl, substitutedpolyaryl, C1-C20 cyclic, substituted C1-C20 cyclic, heterocyclic,substituted heterocyclic, amino acid, peptide, polyether, polyester,polypeptide, protein, polyphosphazene, polyalkylene oxide, polyalkyleneglycol, polyethylene glycol, polyalkylene, a bioactive agent, or a drugmolecule.

In another embodiment, the composition described herein can be amyricitrin derivative of Formula IV:

in which R₁-R₁₃ and Z₁-Z₃ substituents are defined as follows:

R₁, R₆, and R₈ taken independently can be, for example, absence,hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule;

R₂, R₃, R₄, R₅, R₇, R₉, R₁₀, R₁, R₁₂ and R₁₃ taken independently can be,for example, hydrogen, halo, alkyl, substituted alkyl, alkoxy,cycloalkyl, heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, thiol, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, cyano, isocyano, substitutedisocyano, carbonyl, substituted carbonyl, carboxyl, substitutedcarboxyl, amino, substituted amino, amido, substituted amido, fulfonyl,substituted sulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic,substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, polyether, polyester, polypeptide, protein,polyphosphazene, polyalkylene oxide, polyalkylene glycol, polyethyleneglycol, polyalkylene, a bioactive agent, or a drug molecule;

Z₁, Z₂ and Z₃ taken independently can be, for example, oxygen (O),sulphur (S), or NH; and

Z₁ and R₁ taken together can be, for example, a moiety of formula III:

in which R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₁₈ taken independently can be forexample, hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule.

In some embodiments, any of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R₁₂, R₁₃, Z₁, Z₂ and Z₃ of Formula IV can exclude any of the groupsprovided herein. For example, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀,R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, R₁₈, Z₁, Z₂, Z₃ and Z₄ of Formula IVtaken together do not form any of the myricetin derivative as shown inFIG. 1B.

Some other representative myricitrin derivatives are listed in Table 1.

TABLE 1 Some exemplary structures of myricitrin derivatives Compound/Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

In some embodiments, the composition described herein specificallyexclude myricetin (FIG. 1B) or a derivative thereof. In some otherembodiments, the composition described herein may specifically includemyricetin and/or a derivative thereof.

In still some other embodiments, the composition described herein caninclude a mixture of at least two of the various compounds describedabove. For example, the composition may include myricetin (FIG. 1B) andmyricitrin (FIG. 1A) and/or any of other compounds of formulae I, II,and IV described above. Compounds of formula II include compounds offormulae IIa, IIb, IIc, IId, and IIe and compounds as described in Table1.

Formulation carriers

The composition described herein may be administered to a subject inneed of treatment by a variety of routes of administration, includingorally and parenterally, (e.g., intravenously, subcutaneously orintramedullary), intranasally, as a suppository or using a “flash”formulation, i.e., allowing the medication to dissolve in the mouthwithout the need to use water, topically, intradermally, subcutaneouslyand/or administration via mucosal routes in liquid or solid form. Thecomposition can be formulated into a variety of dosage forms, e.g.,extract, pills, tablets, microparticles, capsules, oral liquid.

There may also be included as part of the composition pharmaceuticallyor physiologically acceptable compatible binding agents, and/or adjuvantmaterials. The active materials can also be mixed with other activematerials including antibiotics, antifungals, other virucidals andimmunostimulants which do not impair the desired action and/orsupplement the desired action.

In one embodiment, the mode of administration of the compositiondescribed herein is oral. Oral compositions generally include an inertdiluent or an edible carrier. They may be enclosed in gelatin capsulesor compressed into tablets. For the purpose of oral therapeuticadministration, the aforesaid compounds may be incorporated withexcipients and used in the form of tablets, troches, capsules, elixirs,suspensions, syrups, wafers, chewing gums and the like. In general, aneffective dosage for myricitrin or a derivative thereof, e.g., compoundsof Formulae I or III, described above, is in the range of 0.01 mg/kg/dayto 100 mg/kg/day, preferably 0.01 mg/kg/day to 50 mg/kg/day in single ordivided doses. Some variation in dosage will necessarily occur, however,depending on the condition of the subject being treated. Thesepreparations should produce a serum concentration of active ingredientof from about 0.01 nM to 1,000,000 nM, e.g., from about 0.2 to 40 μM. Apreferred concentration range is from 0.2 to 20 μM and most preferablyabout 1 to 10 μM. However, the concentration of active ingredient in thedrug composition itself depends on bioavailability of the drug and otherfactors known to those of skill in the art.

In another embodiment, the mode of administration of the compositionsdescribed herein is topical or mucosal administration. A specificallypreferred mode of mucosal administration is administration via femalegenital tract. Another preferred mode of mucosal administration isrectal administration.

Various polymeric and/or non-polymeric materials can be used asadjuvants for enhancing mucoadhesiveness of the composition disclosedherein. The polymeric material suitable as adjuvants can be natural orsynthetic polymers. Representative natural polymers include, forexample, starch, chitosan, collagen, sugar, gelatin, pectin, alginate,karya gum, methylcellulose, carboxymethylcellulose,methylethylcellulose, and hydroxypropylcellulose. Representativesynthetic polymers include, for example, poly(acrylic acid), tragacanth,poly(methyl vinylether-co-maleic anhydride), poly(ethylene oxide),carbopol, poly(vinyl pyrrolidine), poly(ethylene glycol), poly(vinylalcohol), poly(hydroxyethylmethylacrylate), and polycarbophil. Otherbioadhesive materials available in the art of drug formulation can alsobe used (see, for example, Bioadhesion—Possibilities and Future Trends,Gurny and Junginger, eds., 1990).

It is to be noted that dosage values also varies with the specificseverity of the disease condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted to the individual need and the professional judgmentof the person administering or supervising the administration of theaforesaid compositions. It is to be further understood that theconcentration ranges set forth herein are exemplary only and they do notlimit the scope or practice of the invention. The active ingredient maybe administered at once, or may be divided into a number of smallerdoses to be administered at varying intervals of time.

The formulation may contain the following ingredients: a binder such asmicrocrystalline cellulose, gum tragacanth or gelatin; an excipient suchas starch or lactose, a disintegrating agent such as alginic acid,Primogel, corn starch and the like; a lubricant such as magnesiumstearate or Sterotes; a glidant such as colloidal silicon dioxide; and asweetening agent such as sucrose or saccharin or flavoring agent such aspeppermint, methyl salicylate, or orange flavoring may be added. Whenthe dosage unit form is a capsule, it may contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, for example, as coatings. Thus tabletsor pills may be coated with sugar, shellac, or other enteric coatingagents. Materials used in preparing these various compositions should bepharmaceutically or physiologically pure and non-toxic in the amountsused.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethylparabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parental preparationcan be enclosed in ampoules, disposable syringes or multiple dose vialsmade of glass or plastic.

The compositions of the present invention are prepared as formulationswith pharmaceutically or physiologically acceptable carriers. Preferredare those carriers that will protect the active compound against rapidelimination from the body, such as a controlled release formulation,including implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such aspolyanhydrides, polyglycolic acid, collagen, and polylactic acid.Methods for preparation of such formulations can be readily performed byone skilled in the art.

Liposomal suspensions (including liposomes targeted to infected cellswith monoclonal antibodies to viral antigens) are also preferred aspharmaceutically or physiologically acceptable carriers. Methods forencapsulation or incorporation of compounds into liposomes are describedby Cozzani, I.; Jori, G.; Bertoloni, G.; Milanesi, C.; Sicuro, T. Chem.Biol. Interact. 53, 131-143 (1985) and by Jori, G.; Tomio, L.; Reddi,E.; Rossi, E. Br. J. Cancer 48, 307-309 (1983). These may also beprepared according to methods known to those skilled in the art, forexample, as described in U.S. Pat. No. 4,522,811 (which is incorporatedherein by reference in its entirety). For example, liposome formulationsmay be prepared by dissolving appropriate lipid(s) (such as stearoylphosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachidoylphosphatidyl choline, and cholesterol) in an inorganic solvent that isthen evaporated, leaving behind a thin film of dried lipid on thesurface of the container. An aqueous solution of the active compound isthen introduced into the container. The container is then swirled byhand to free lipid material from the sides of the container and todisperse lipid aggregates, thereby forming the liposomal suspension.

Other methods for encapsulating compounds within liposomes and targetingareas of the body are described by Sicuro, T.; Scarcelli, V.; Vigna, M.F.; Cozzani, I. Med. Biol. Environ. 15(1), 67-70 (1987) and Jori, G.;Reddi, E.; Cozzani, I.; Tomio, L. Br. J. Cancer, 53(5), 615-21 (1986).

The composition described herein may be administered in single (e.g.,once daily) or multiple doses or via constant infusion. The compounds ofthis invention may also be administered alone or in combination withpharmaceutically or physiologically acceptable carriers, vehicles ordiluents, in either single or multiple doses. Suitable pharmaceutical orphysiologically carriers, vehicles and diluents include inert soliddiluents or fillers, sterile aqueous solutions and various organicsolvents. The compositions described herein are then readilyadministered in a variety of dosage forms such as tablets, powders,lozenges, syrups, injectable solutions and the like. Thesepharmaceutical compositions can, if desired, contain additionalingredients such as flavorings, binders, excipients and the likeaccording to a specific dosage form.

Thus, for example, for purposes of oral administration, tabletscontaining various excipients such as sodium citrate, calcium carbonateand/or calcium phosphate may be employed along with variousdisintegrants such as starch, alginic acid and/or certain complexsilicates, together with binding agents such as polyvinylpyrrolidone,sucrose, gelatin and/or acacia. Additionally, lubricating agents such asmagnesium stearate, sodium lauryl sulfate and talc are often useful fortabletting purposes. Solid compositions of a similar type may also beemployed as fillers in soft and hard filled gelatin capsules. Preferredmaterials for this include lactose or milk sugar and high molecularweight polyethylene glycols. When aqueous suspensions or elixirs aredesired for oral administration, the active pharmaceutical/physiologicalagent therein may be combined with various sweetening or flavoringagents, coloring matter or dyes and, if desired, emulsifying orsuspending agents, together with diluents such as water, ethanol,propylene glycol, glycerin and/or combinations thereof.

For parenteral administration, solutions of the compounds of thisinvention in sesame or peanut oil, aqueous propylene glycol, or insterile aqueous solutions may be employed. Such aqueous solutions shouldbe suitably buffered if necessary and the liquid diluent first renderedisotonic with sufficient saline or glucose. These particular aqueoussolutions are especially suitable for intravenous, intramuscular,subcutaneous and intraperitoneal administration. In this connection, thesterile aqueous media employed are all readily available by standardtechniques known to those skilled in the art.

For intranasal administration or administration by inhalation, thecompounds of the invention are conveniently delivered in the form of asolution or suspension from a pump spray container that is squeezed orpumped by the patient or as an aerosol spray presentation from apressurized container or a nebulizer, with the use of a suitablepropellant, e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. The pressurized containeror nebulizer may contain a solution or suspension of a compound of thisinvention. Capsules and cartridges (made, for example, from gelatin) foruse in an inhaler or insufflator may be formulated containing a powdermix of a compound or compounds of the invention and a suitable powderbase such as lactose or starch.

The composition provided herein can also be used with anotherpharmaceutically or physiologically active agent effective for a diseasesuch as neurodisorders, cardiovascular disorders, tumors, AIDS,depression, and/or type-1 and type-2 diabetes. Such additional agentscan be, for example, antiviral agent, antibiotics, anti-depressionagent, anti-cancer agents, immunosuppressant, anti-fungal, and acombination thereof.

The composition described herein can be formulated alone or togetherwith the other agent in a single dosage form or in a separate dosageform. Methods of preparing various formulations with a certain amount ofactive ingredient are known, or will be apparent in light of thisdisclosure, to those skilled in this art. For examples of methods ofpreparing pharmaceutical formulations, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

Methods of Use

The composition described herein can be used for treating, preventing orameliorating the above described conditions in a mammal, including ahuman. The composition can be administered as part of an appropriatedosage regimen designed to obtain the benefits of the therapy. Theappropriate dosage regimen, the amount of each dose administered and theintervals between doses of the compound will depend upon the compound ofFormulae I, II or IV of this invention being used, the type ofpharmaceutical compositions being used, the characteristics of thesubject being treated and the severity of the conditions.

The compounds of Formulae I, II or IV of the present invention areuseful for the treatment of insomnia, depression-related disease,stress-related disease, depression-related sleep disorder, andneurodegeneration diseases such as Alzheimer's disease, Pick's disease,spinocerbellar degeneration, Parkinson's disease, chorea, glaucoma,amyotrophic lateral sclerosis, senile macular degeneration, hepaticencephalopathy, demyelinating diseases, Lewy body dementia,multi-infarct dementia, multiple sclerosis.

The term “depression-related disease” means a disease caused by anabnormally low serotonin level in the synapse. Examples of such adisease include seasonal affective disorder, premenstrual syndrome,unipolar depression, bipolar depression, manic-depressive psychosis andatypical depression and depression-related sleep-disorder.

The “stress-related disease” is also caused by an abnormally lowserotonin level, and examples thereof include depression, posttraumaticstress disorder, stress-related bodily disorders like idiopathic painsyndromes and chronic fatigue syndrome.

The term “depression-related sleep disorder” means a sleep disorderwhich is caused by dysfunction of the serotonin and melatonin system.Examples of such a disease include insomnia, hypersomnia, parasomnia,dysomnia, fibromyalgia, jetleg, shift-work sleep disorder, delayed-sleepphase syndrome, and advanced-sleep phase syndrome.

The term “neurodegeneration disease” refers to a disorder in which neurodegeneration is involved. Examples of such a disease include Alzheimer'sdisease, Pick's disease, spinocerbellar degeneration, Parkinson'sdisease, chorea, glaucoma, amyotrophic lateral sclerosis, senile maculardegeneration, hepatic encephalopathy, demyelinating diseases, Lewy bodydementia, multi-infarct dementia, multiple sclerosis.

Methods of Making Myricitrin and Related Compounds

Myricitrin is a plant flavinoid found in numerous herbs such as; witchhazel (Hamameliadaceae hamamelis Virginia), bayberry (Myrica cerifera);Corylus avellana L. and Myrtaceae and can be readily isolated from aplant or herb such as the ones listed below in Table 2.

TABLE 2 List of plants containing myricitrin Species Part Araucariabidwillii HOOK. [Araucariaceae] Plant Ardisia japonica L. [Myrsinaceae]Leaf Caesalpinia pulcherrima (L.) SW. [Fabaceae] Plant Catha edulis VAHL[Celastraceae] Plant Corylus avellana L. [Betulaceae] Leaf Corylusavellana L. [Betulaceae] Bark Juglans nigra L. [Juglandaceae] FruitLiquidambar styraciflua L. [Hamamelidaceae] Leaf Myrica cerifera L.[Myricaceae] Plant Myrtus communis L. [Myrtaceae] Plant Ononis spinosaL. [Fabaceae] Shoot Rhus coriaria L. [Anacardiaceae] Leaf Desmanthusillinoensis [Family: Fabaceae (bean family); subfamily: Mimosoideae(mimosa) Arctostaphylos uva ursi(also known as Uvae ursi folium,Arctostaphylos, bearberry, and beargrape) Polygonum aviculare HerbaArdisiae JaPonicae Cotinus coggygria Scop. var. cinerea Engl.[Anacardiaceae] Witch Hazel Hamamelis virginiana [Hamameliadaceae]

Myricitrin derivatives can be synthesized via methods known in the artof medicinal chemistry and/or organic synthesis (see, for example, RolfCarlson, Design and Optimization in Organic Synthesis, Elsevier; W. A.Smit, et al., The Science behind The Art, 1998).

Some representative methods of making compounds of formulae I, II or IVare provided in the schemes shown in FIGS. 2-5 (see also, Journal ofNatural Products, 64(4), 462-465 (2001); Khimiya Prirodnykh Soedinenii,(2), 274-6 (1990); Zhiwu Xuebao, 31(3), 205-8 (1989); Chemical &Pharmaceutical Bulletin, 50(6), 788-795 (2002); and Perkin 2 (9),1946-1952 (2000)).

The following non-limiting examples illustrate a few embodiments of thepresent invention.

EXAMPLES Example 1 Effects of Mixtures of Dihydromyricetin, Myricetinand Myricitrin on Loss of Righting Reflex in Male C57/B6 Mice

C57/B6 mice were randomised into groups and orally administered.Compound mixtures-1, -2, -3 (Table 3), which are mixtures ofdihydromyricetin (compound A), myricetin (compound B) and myricitrin(compound C), or vehicle 60 min prior to low dose injection of sodiumpentobarbitone (12.5 mg/kg, i.p.).

TABLE 3 Compound mixture compositions Compound Mixture-1: 90.38% A 7.77%B 1.84% C Compound Mixture-2: 95.14% A 3.69% B 1.23% C CompoundMixture-3: 75.46% A 23.26% B  1.27% CThe animals were then placed on a heating pad (37° C.) and theirduration of sleep was then determined according to loss of rightingreflex. FIG. 6 shows loss of righting reflex in male C57/B6 micefollowing oral treatment of compound mixtures-1, -2 and -3 (50 mg/kg,p.o.) versus vehicle (10 ml/kg, H₂O, p.o), 1 hour prior to pentobarbital(12.5 mg/kg, i.p.) injection. Data were analysed by unpaired t-testversus vehicle treated group (**p<0.01, ****p<0.001, n>11).

These test results demonstrated that all extracts containing differentratios of compounds A, B and C were able to significantly prolongpentobarbital induced-sleeping time, with compound mixture-3 having thegreatest effect (FIG. 6). The results seem to be reflective of theratios of the active compounds within each mixture, with the extractcontaining almost equal balance of A and B (mixture-3) being mosteffective.

Example 2 Telemetry Studies in Freely Moving Male Wistar Rats Comparisonof the Effects of Compound Mixture, Zolpidem and Zopiclone VersusVehicle Treatment on Sleep Latency and Quality

Telemetric EEG, activity and temperature monitors were surgicallyimplanted sub-coetaneously onto the lower backs of male Wistar rats,under ketamie and xyalsine (75/10 mg/kg, i.p.) anaesthesia. A skinincision was made above the scull and the transmitter tunneledsubcutaneously from the neck to the lower back with blunted scissors.The EEG leads were placed into two 0.5 mm holes that were drilledstererotaxically 2 mm anterior to Lambda and 1 mm to the left and rightof centre, so that contact was made with the durra, and fixed with quickdrying glue and reinforced with dental cement. The incision was thenclosed with 4-0 silk suture and post operative temgesic applied for painrelief. Following a 4 week recovery and acclimatization period inindividually housed ventilated cages (12 hour light/12 hour dark cycle20-25° C.), the rats were orally treated with either test compounds,positive controls or vehicle 45-30 min prior commencement of their lightcycle (sleeping period). A Latin square dosing regiment was used whereeach rat received each of the drugs tested in random order with 4 daysclearance time between each dosing. EEG waveforms were analysed using apower spectral analysis of each 5 second epoch and scored manually into% duration of NREM sleep for each hour over a 12 hour period.

FIGS. 7A-7C shows the duration of NREM sleep induced by zolpidem (5mg/kg, p.o., FIG. 7A), zopiclone (5 mg/kg, p.o., FIG. 7B) or CompoundMixture (50 mg/kg, p.o., FIG. 7C), which is a mixture ofdihydromyricetin (compound A), myricetin (compound B) and myricitrin(compound C) (A/B/C=1:0.1:0.08) in male Wistar rats during 12-hour lightcycle. Data were analysed using Two-way ANOVA versus vehicle treatment(*p<0.05, n=7).

As shown in FIGS. 7A-7C, zolpidem (5 mg/kg, p.o., FIG. 7A), Zopiclone (5mg/kg, p.o., FIG. 7B) and the Compound Mixture (FIG. 7C) allsignificantly increased NREM sleep within the first hour followingtreatment, indicating that they were able to significantly reduce sleeplatency compared to vehicle treatment. During the second hour followingtreatment, compound mixture (FIG. 7C) continued to maintain longdurations of NREM sleep, whereas zolpidem and zopiclone (FIGS. 7A and7B) were not significantly different from vehicle treatment. During theremainder of the sleep period, zolpidem (FIG. 7A) failed tosignificantly improve NREM sleep compared to vehicle, whereas zopiclone(FIG. 7B) only significantly improved NREM sleep duration during the8^(th) hour, but had a negative effect on sleep quality during the6^(th) hour of sleep. Conversely, Compound Mixture (FIG. 7C) was alsoable to significantly improve NREM sleep during the 7^(th) and 8^(th)hour of sleep and had no observed detrimental effect on NREM durationduring the course of the sleep period.

Further tests showed that compound mixtures of A:B:C in the ratios of1-2:0.1-0.12:0.05-0.08 all showed similar results in telemetry rats.

The present data indicate that the Compound Mixture is able tosignificantly reduce sleep latency with a similar effect to existingsedatives zolpidem and zopiclone in rats. Furthermore the CompoundMixture is able to maintain longer periods of NREM sleep during thesleep period and thus attain a deeper sleep than both zolpidem andzopiclone, indicating that the Compound Mixture may be beneficial forimproving the quality of sleep.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method of treating, preventing, or ameliorating insomnia or anothersleeping disorder in a human subject, comprising administering to thesubject an effective amount of a composition comprising a compound offormulae I, II, or IV, the compound being effective for treating,preventing, or ameliorating insomnia or a sleeping disorder related to adisorder selected from the group consisting of depression-relateddisease, stress-related disease, depression-related sleep disorder,neurodegeneration diseases, Alzheimer's disease, Pick's disease,spinocerbellar degeneration, Parkinson's disease, chorea, glaucoma,amyotrophic lateral sclerosis, senile macular degeneration, hepaticencephalopathy, demyelinating diseases, Lewy body dementia,multi-infarct dementia, multiple sclerosis and combinations thereof,wherein the compound of formulae I or II has a structure of

in which: R₁, R₂, and R₁₂ taken independently are selected from absence,hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; R₃, R₄, R₅, R₆, R₇,R₈, R₉, R₁₀, R₁₁, R₁₃ and R₂₀ taken independently are selected fromhydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; Z₁, Z₂ and Z₃ takenindependently are oxygen (O), sulphur (S), or NH; Z₁ and R₁ takentogether are a moiety of formula III:

where R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ taken independently are selectedfrom hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; and Z₄ is oxygen(O), sulphur (S), or NH, wherein the compound of Formula II is notmyricetin, wherein the compound of Formula IV has a structure of inwhich:

R₁, R₆, and R₈ taken independently are selected from absence, hydrogen,halo, alkyl, substituted alkyl, alkoxy, cycloalkyl, heterocyclic,alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, phenyl, substituted phenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, hydroxyl, alkoxy, substituted alkoxy, phenoxy,substituted phenoxy, aroxy, substituted aroxy, thiol, alkylthio,substituted alkylthio, phenylthio, substituted phenylthio, arylthio,substituted arylthio, cyano, isocyano, substituted isocyano, carbonyl,substituted carbonyl, carboxyl, substituted carboxyl, amino, substitutedamino, amido, substituted amido, fulfonyl, substituted sulfonyl,polyaryl, substituted polyaryl, C1-C20 cyclic, substituted C1-C20cyclic, heterocyclic, substituted heterocyclic, amino acid, peptide,polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; R₂, R₃, R₄, R₅, R₇,R₉, R₁₀, R₁₁, R₁₂ and R₁₃ taken independently are selected fromhydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; Z₁, Z₂ and Z₃ takenindependently are selected from oxygen (O), sulphur (S), or NH; and Z₁and R₁ taken together are a moiety of formula III:

in which R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₁₈ taken independently areselected from hydrogen, halo, alkyl, substituted alkyl, alkoxy,cycloalkyl, heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, thiol, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, cyano, isocyano, substitutedisocyano, carbonyl, substituted carbonyl, carboxyl, substitutedcarboxyl, amino, substituted amino, amido, substituted amido, fulfonyl,substituted sulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic,substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, polyether, polyester, polypeptide, protein,polyphosphazene, polyalkylene oxide, polyalkylene glycol, polyethyleneglycol, polyalkylene, a bioactive agent, or a drug molecule.
 2. Themethod of claim 1, wherein the compound of Formula I is myricitrin. 3.The method of claim 1, wherein the compound of formula II is in aracemic form, a mixture of diastero isomers, or an enantiomer.
 4. Themethod of claim 3, wherein the enantiomer has a structure as shown informulae IIa, IIb, IIc and IId:

in which: R₁, R₂, and R₁₂ taken independently are selected from absence,hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; R₃, R₄, R₅, R₆, R₇,R₈, R₉, R₁₀, R₁₁, R₁₃ and R₂₀ taken independently are selected fromhydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; Z₁, Z₂ and Z₃ takenindependently are oxygen (O), sulphur (S), or NH; Z₁ and R₁ takentogether is a moiety of formula III:

where R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ taken independently are selectedfrom hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; and Z₄ is oxygen(O), sulphur (S), or NH.
 5. The method of claim 1, wherein the compoundof formula II is a compound of formula IIe:

in which R₁ is selected from hydrogen, halo, alkyl, substituted alkyl,alkoxy, cycloalkyl, heterocyclic, alkenyl alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, thiol, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, cyano, isocyano, substitutedisocyano, carbonyl, substituted carbonyl, carboxyl, substitutedcarboxyl, amino, substituted amino, amido, substituted amido, fulfonyl,substituted sulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic,substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, polyether, polyester, polypeptide, protein,polyphosphazene, polyalkylene oxide, polyalkylene glycol, polyethyleneglycol, polyalkylene, a bioactive agent, or a drug molecule.
 6. A methodof treating, preventing, or ameliorating insomnia or another sleepingdisorder in a human subject, comprising administering to the subject acomposition comprising at least two compounds of formula I, II or IV,the compounds being effective for treating, preventing, or amelioratinginsomnia or a sleeping disorder related to a disorder selected from thegroup consisting of depression-related disease, stress-related disease,depression-related sleep disorder, neurodegeneration diseases,Alzheimer's disease, Pick's disease, spinocerbellar degeneration,Parkinson's disease, chorea, glaucoma, amyotrophic lateral sclerosis,senile macular degeneration, hepatic encephalopathy, demyelinatingdiseases, Lewy body dementia, multi-infarct dementia, multiple sclerosisand combinations thereof, wherein the compound of formulae I or II has astructure of

in which: R₁, R₂, and R₁₂ taken independently are selected from absence,hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; R₃, R₄, R₅, R₆, R₇,R₈, R₉, R₁₀, R₁₁, R₁₃ and R₂₀ taken independently are selected fromhydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; Z₁, Z₂ and Z₃ takenindependently are oxygen (O), sulphur (S), or NH; Z₁ and R₁ takentogether are a moiety of formula III: where

R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ taken independently are selected fromhydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; and Z₄ is oxygen(O), sulphur (S), or NH, wherein the compound of Formula IV has astructure of

in which: R₁, R₆, and R₈ taken independently are selected from absence,hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; R₂, R₃, R₄, R₅, R₇,R₉, R₁₀, R₁₁, R₁₂ and R₁₃ taken independently are selected fromhydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; Z₁, Z₂ and Z₃ takenindependently are oxygen (O), sulphur (S), or NH; and Z₁ and R₁ takentogether are a moiety of formula III:

in which R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₁₈ taken independently areselected from hydrogen, halo, alkyl, substituted alkyl, alkoxy,cycloalkyl, heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, thiol, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, cyano, isocyano, substitutedisocyano, carbonyl, substituted carbonyl, carboxyl, substitutedcarboxyl, amino, substituted amino, amido, substituted amido, fulfonyl,substituted sulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic,substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, polyether, polyester, polypeptide, protein,polyphosphazene, polyalkylene oxide, polyalkylene glycol, polyethyleneglycol, polyalkylene, a bioactive agent, or a drug molecule.
 7. Themethod of claim 6, wherein the compound of Formula I is myricitrin, andwherein the compound of Formula II is dihydro-myricetin.
 8. The methodof claim 6, wherein the compound of formula II is in a racemic form, amixture of diastero isomers, or an enantiomer.
 9. The method of claim 8,wherein the enantiomer has a structure as shown in formulae IIa, IIb,IIc and IId:

in which: R₁, R₂, and R₁₂ taken independently are selected from absence,hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; R₃, R₄, R₅, R₆, R₇,R₈, R₉, R₁₀, R₁₁, R₁₃ and R₂₀ taken independently are selected fromhydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; Z₁, Z₂ and Z₃ takenindependently are oxygen (O), sulphur (S), or NH; Z₁ and R₁ takentogether are a moiety of formula III:

where R₁₄, R₁₅, R₁₆, R₁₇, R₁₈ and R₁₉ taken independently are selectedfrom hydrogen, halo, alkyl, substituted alkyl, alkoxy, cycloalkyl,heterocyclic, alkenyl alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, phenyl, substituted phenyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, hydroxyl, alkoxy, substitutedalkoxy, phenoxy, substituted phenoxy, aroxy, substituted aroxy, thiol,alkylthio, substituted alkylthio, phenylthio, substituted phenylthio,arylthio, substituted arylthio, cyano, isocyano, substituted isocyano,carbonyl, substituted carbonyl, carboxyl, substituted carboxyl, amino,substituted amino, amido, substituted amido, fulfonyl, substitutedsulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic, substitutedC1-C20 cyclic, heterocyclic, substituted heterocyclic, amino acid,peptide, polyether, polyester, polypeptide, protein, polyphosphazene,polyalkylene oxide, polyalkylene glycol, polyethylene glycol,polyalkylene, a bioactive agent, or a drug molecule; and Z₄ is oxygen(O), sulphur (S), or NH.
 10. The method of claim 6, wherein the compoundof formula II is a compound of formula IIe:

in which R₁ is selected from hydrogen, halo, alkyl, substituted alkyl,alkoxy, cycloalkyl, heterocyclic, alkenyl alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, phenyl, substituted phenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, hydroxyl, alkoxy,substituted alkoxy, phenoxy, substituted phenoxy, aroxy, substitutedaroxy, thiol, alkylthio, substituted alkylthio, phenylthio, substitutedphenylthio, arylthio, substituted arylthio, cyano, isocyano, substitutedisocyano, carbonyl, substituted carbonyl, carboxyl, substitutedcarboxyl, amino, substituted amino, amido, substituted amido, fulfonyl,substituted sulfonyl, polyaryl, substituted polyaryl, C1-C20 cyclic,substituted C1-C20 cyclic, heterocyclic, substituted heterocyclic, aminoacid, peptide, polyether, polyester, polypeptide, protein,polyphosphazene, polyalkylene oxide, polyalkylene glycol, polyethyleneglycol, polyalkylene, a bioactive agent, or a drug molecule.
 11. Themethod of claim 1, further comprising a pharmaceutically acceptablecarrier.
 12. The method of claim 6, further comprising apharmaceutically acceptable carrier.
 13. The method of claim 1, furthercomprising an agent selected from the group consisting of antiviralagent, antibiotics, anti-depression agent, anti-cancer agents,immunosuppressant, anti-fungal, and a combination thereof.
 14. Themethod of claim 6, further comprising an agent selected from the groupconsisting of antiviral agent, antibiotics, anti-depression agent,anti-cancer agents, immunosuppressant, anti-fungal, and a combinationthereof.
 15. The method of claim 11, wherein the pharmaceuticallyacceptable carrier is a carrier suitable for oral delivery, parenteraldelivery, topical delivery, mucosal delivery, intradermal delivery,intravenous injection, subcutaneous injection, intramedullary injection,administration by inhalation, and intranasal delivery.
 16. The method ofclaim 12, wherein the pharmaceutically acceptable carrier is a carriersuitable for oral delivery, parenteral delivery, topical delivery,mucosal delivery, intradermal delivery, intravenous injection,subcutaneous injection, intramedullary injection, administration byinhalation, and intranasal delivery.
 17. The method of claim 15 in adosage form selected from the group consisting of a solution, asuspension, a syrup, a tablet, a capsule, microparticles, an ointment, acream, and a lozenge.
 18. The method of claim 16 in a dosage formselected from the group consisting of a solution, a suspension, a syrup,a tablet, a capsule, microparticles, an ointment, a cream, and alozenge.